Going to extremes: progress in exploring new environments for novel antibiotics.

The discoveries of penicillin and streptomycin were pivotal for infection control with the knowledge subsequently being used to enable the discovery of many other antibiotics currently used in clinical practice. These valuable compounds are generally derived from mesophilic soil microorganisms, predominantly Streptomyces species. Unfortunately, problems with the replication of results suggested that this discovery strategy was no longer viable, motivating a switch to combinatorial chemistry in conjunction with existing screening programmes to derive new antimicrobials. However, the chemical space occupied by these synthetic products is vastly reduced compared to those of natural products. More recent approaches such as using artificial intelligence to 'design' synthetic ligands to dock with molecular targets suggest that chemical synthesis is still a promising option for discovery. It is important to employ diverse discovery strategies to combat the worrying increase in antimicrobial resistance (AMR). Here, we reconsider whether nature can supply innovative solutions to recalcitrant infections. Specifically, we assess progress in identifying novel antibiotic-producing organisms from extreme and unusual environments. Many of these organisms have adapted physiologies which often means they produce different repertoires of bioactive metabolites compared to their mesophilic counterparts, including antibiotics. In addition, we examine insights into the regulation of extremotolerant bacterial physiologies that can be harnessed to increase the production of clinically important antibiotics and stimulate the synthesis of new antibiotics in mesophilic microorganisms. Finally, we comment on the insights provided by combinatorial approaches to the treatment of infectious diseases that might enhance the efficacy of antibiotics and reduce the development of AMR.